Several clinical studies have detected an unexpected inhibition of diabetic retinopathy by ACE (angiotensin-converting enzyme) inhibitors, and the mechanism for this action is unclear. In light of evidence indicating that the severity of hyperglycemia is a major initiating factor in the pathogenesis of retinopathy, we have examined the effect of ACE inhibitor captopril on glucose level in the retina of diabetic rats. Our preliminary data suggest that captopril inhibits diabetes-induced accumulation of glucose in the retina of diabetic rats. Likewise, captopril significantly inhibits intracellular glucose accumulation in retinal cells cultured in elevated glucose concentration, indicating that inhibition of glucose accumulation in retinal tissue is not due solely to reduction in blood pressure or in vascular permeability. Sorbitol, which can be produced within cells when intracellular glucose is elevated, likewise is increased in the retina in diabetes, and inhibited by captopril, further demonstrating that glucose is elevated intracellularly in the retina of diabetic rats and that captopril inhibits the accumulation of glucose. These findings suggest the overall hypothesis that beneficial effects of ACE inhibitors on the development of diabetic retinopathy might result in part from inhibition of intracellular glucose accumulation in retinas, thus restricting the activation of metabolic sequelae of hyperglycemia. The proposed project is going to determine if inhibition of glucose accumulation in the diabetic retina is characteristic of antihypertensive medications in general, or is unique to one class of antihypertensive drugs, or to one drug and to investigate the mechanism by which the ACE inhibitor inhibits intracellular glucose accumulation. Inhibition of glucose accumulation represents a novel mechanism for the observed beneficial effect of ACE inhibitors on the development of diabetic retinopathy. We believe that agents having this effect can be characterized and improved, offering an additional pharmacologic means to inhibit the development and progression of diabetic retinopathy.